As used herein, “sustained release” of a treating agent means that the treating agent is released over a period of time, e.g., over 6 hours or 24 hours or 72 hours, rather than almost immediately. “Controlled release” is a different issue. A drug could be released over 72 hours, but hour-to-hour variation in the rate of release could be random, for example, 600% or more. Such a formulation would be characterized as sustained but not controlled (unless the particular pattern of release was by design, and not random). The objective, which is met by using an emulsion system, is not only to sustain the effect but also to control it—to provide a rate of release in a controlled manner, often a steady rate of release, but optionally with predetermined, purposeful changes in the release rate over time. The result is a sustained, controlled release.
In previous formulations, polycarbophil and similar polymers have been utilized to sustain the action of drugs using an emulsion system to control their release. In the case of terbutaline sulfate and progesterone, the controlled, sustained release is provided by use of an emulsion system. We previously demonstrated controlled, apparent-zero-order release, i.e., a constant quantity of drug is released per unit of time, for these formulations. The previous compositions, however, all included an oil phase using an emulsion system.
Examples of our prior formulations having an oil phase and water phase include the following: the terbutaline formulations as disclosed in U.S. Pat. No. 6,126,959 and U.S. patent application Ser. No. 09/510,527; and progesterone or progestin formulations as disclosed in U.S. Pat. Nos. 5,543,150; 5,985,861; 6,054,447; 6,306,914; and 6,593,317.
Specific examples of these formulations, containing both an oil and water phase follow.
The progesterone formula is:Carbopol (carbomer) 974P1.00%NOVEON ® AA1 (polycarbophil)2.00%Glycerin12.90%Vestran (Light liquid paraffin)4.20%Myverol1.00%Sorbic Acid0.08%Progesterone8.00%Water70.82%The terbutaline formula is:Terbutaline sulfate0.40%Carbopol 974P3.00%Polycarbophil2.00%Glycerin12.90%Light liquid paraffin4.20%Polyglycosyl glycerides (Labrafil)1.00%Methyl paraben0.18%Sorbic Acid0.08%Water76.24%
Other patents and applications that disclose polycarbophil formulations having a treating agent that use both oil and water phases include, U.S. Pat. Nos. 4,615,697; 4,795,436; 4,983,392; 5,225,196; 5,474,768; 5,667,492; and 5,968,500; and U.S. application Ser. Nos. 09/593,603 and 10/089,796.
U.S. patent application Ser. No. 09/877,218 discloses several terbutaline formulations that do not contain an oil phase. In that application, terbutaline is in the wet granulate form, which is subsequently dried. The polymers are only mixed in after the granulate has been dried. Thus, the terbutaline formulation does not hydrate and form a complex between the polymer and the treating agent as in the present invention. Accordingly, these terbutaline formulations provide sustained, controlled release of the treating agent via a different mechanism then the present invention.
Polyacrylic acid polymers have been used to form insoluble complexes for other purposes in the past. For example, U.S. Pat. No. 3,427,379 discloses that dextromethorphan HCl can be complexed with a polyacrylic acid polymer, specifically carbomer 934P, to overcome its unpleasant bitter taste, as insoluble drugs have no taste. In this case, the complex is created in a tasteless pharmaceutical formulation, such as a suspension, that is then swallowed. As soon as the product is swallowed and reaches the acidic environment of the stomach the polyacrylic acid polymer is re-protonated and all of the dextromethorphan is made available to be absorbed immediately. The sole purpose of the invention of the '379 patent is to mask the bitter taste; it does not sustain or control the release of dextromethorphan.
Progesterone is partially soluble in the oil and water phases with the majority in suspension, creating a controlled-release system. In this example, progesterone is stored in the lipophilic fraction and suspended in the gel, thereby creating a reservoir for prolonged release. A small quantity of progesterone is also dissolved in the aqueous phase. From vaginal application, as well as all other routes of administration, only the drug in the aqueous fraction is available for diffusion into the uterus or absorption into the bloodstream. Therefore, for example, progesterone absorption from progesterone gel is not dependent on the presence of adequate local hydration because the progesterone dissolved in the aqueous phase is immediately available. Specifically, progesterone absorption from progesterone gel does not depend on the highly variable degree of vaginal secretions, as is the case for oil-based progesterone products and other non-hydrated formulations.
In an emulsion system the oil and aqueous phases are in dynamic equilibrium. For example, as progesterone diffuses into tissue or blood from the aqueous phase, it is replaced by the progesterone that is stored in the oil phase or suspension reservoir, thus, ensuring a constant and controlled release of progesterone. The polycarbophil based bioadhesive delivery system in progesterone gel ensures a sustained release of progesterone. See FIG. 1A. In these formulations the emulsion system provides the controlled release of the drug, not the polycarbophil.
Several pharmaceutical compositions have been made in an attempt to treat pelvic pain with limited success. Pelvic pain may be intermittent or recurrent, or it may be constant and severe, but it is frequently associated with uterine dysrhythmia—abnormal, disordered, or disturbed contractions of the uterus. Pelvic pain is often experienced during menses, as painful menstruation, or dysmenorrhea. Women with chronic pelvic pain associated with menstruation frequently spend one day each month in bed and also may have an additional day each month of reduced activity because of the severity of the pain. Pelvic pain may also be caused by pelvic infections, and diseases of the urinary tract or bowel.
Infertility also may be associated with uterine dysrhythmic conditions, including dysmenorrhea. See, e.g., U.S. patent application Ser. No. 10/089,796. Uterine dysrhythmias may affect the rapid transport of sperm, thus affecting fertility. Contractility along the female tract (uterus and fallopian tubes) appears to be the primary motor assuring rapid transport of sperm from the cervical area to the distal end of the tubes, where fertilization takes place. Retrograde uterine contractility appears to impede this normal transport mechanism.
Chronic pelvic pain is common in women in the reproductive age group. It causes disability and distress, and results in significant costs to health services. Overall, a woman has about a 5% risk of having chronic pelvic pain for some period of time in her lifetime. In patients with a previous diagnosis of pelvic inflammatory disease this risk is increased fourfold to approximately 20%. Recent epidemiologic data from the United States showed that 14.7% of women in their reproductive ages reported chronic pelvic pain. A total of 15% of these women with chronic pelvic pain reported time lost from work and 45% reported reduced work productivity. In the United States 10% of outpatient gynecologic consultations are for chronic pelvic pain and 40% of laparoscopies are done for chronic pelvic pain.
The pathogenesis of chronic pelvic pain is poorly understood. Often, investigation by laparoscopy may reveal endometriosis, mild to moderate, or it may reveal no obvious cause for pain. There are several possible explanations for chronic pelvic pain including undetected irritable bowel syndrome, the vascular hypothesis where pain is thought to arise from dilated pelvic veins in which blood flow is markedly reduced and altered spinal cord and brain processing of stimuli in women with chronic pelvic pain. As the pathophysiology of chronic pelvic pain is not well understood, its treatment is often unsatisfactory and limited to symptom relief. Currently, the main approaches to treatment include symptomatic treatment of pain with medication, surgery, or possibly psychotherapy and counseling.
Very little is known about effective pharmacologic treatment for chronic pelvic pain, despite the fact that it is a very common chronic pain syndrome. Several different pharmacologic classes of medications have been used to alleviate the symptomatic pain and discomfort, rather than treat or prevent the underlying cause, in patients with chronic pain syndromes: nonsteroidal anti-inflammatory drugs, anticonvulsants, local anesthetics, and opioids. Very few studies have focused on the actual treatment or prevention of the underlying cause—uterine dyskinetic contractions—in order to treat or prevent chronic pelvic pain.
Dysmenorrhea is associated with pain typically related to the menstrual cycle and can be primary or secondary. Most women experience primary dysmenorrhea at some time during their life. The pain is cramping or sharp and lasts the first few days of the menstrual period. It may radiate to the back, thighs, or deep pelvis. Occasionally, nausea or vomiting occurs. Secondary dysmenorrhea may be due to endometriosis or cervical stenosis or, if associated with heavy menstrual flow, to fibroids, adenomyosis, or large endometrial polyps.
In order to provide local or regional blockade for extended periods, clinicians currently use local anesthetics administered through a catheter or syringe to a site where the pain is to be blocked. This requires repeated administration where the pain is to be blocked over a period of greater than one day, either as a bolus or through an indwelling catheter connected to an infusion pump. These methods have the disadvantage of potentially causing irreversible damage to nerves or surrounding tissues due to fluctuations in concentration and high levels of anesthetic. In addition, anesthetic administered by these methods are generally neither confined to the target area, nor delivered in a linear, continuous manner. In all cases, analgesia rarely lasts for longer than six to twelve hours, more typically four to six hours. In the case of a pump, the infusion lines are difficult to position and secure, the patient has limited, encumbered mobility and, when the patient is a small child or mentally impaired, may accidentally disengage the pump.
U.S. Pat. No. 5,700,485 discloses a method and device for administering a local anesthetic combined with a biodegradable polymer incorporated into microspheres. Prolonged release of the anesthetic is obtained by administration with glucocorticoid.
Because high systemic anesthetic concentration can cause irritation or burning to the vagina, as well as other detrimental side effects, there is a need to keep systemic circulation of the anesthesia low. Thus, there is a need for a formulation in which local anesthetics would diffuse preferentially into the cervix for a prolonged period of time to ensure sufficient anesthesia for treating pelvic pain due to dysrhythmic conditions, while keeping systemic circulation low.
Similarly, high systemic levels of other anti-dysrhythmic treating agents may lead to adverse side effects, some of which may be severe. Many classic anti-arrhythmic (and other anti-dysrhythmic) agents themselves have the ability to cause coronary arrhythmia. Other detrimental side effects include without limitation nausea, blurred or yellow vision, precipitation of glaucoma, constipation, seizures, tremor, bone marrow aplasia, pulmonary fibrosis, hypotension, reduction of exercise heart rate, diarrhea and diarrhea-induced hypokalemia, and immunological reactions such as thrombocytopenia, hepatitis, or bone marrow depression. Thus, use of an anti-dysrhythmic agent to treat or prevent uterine dysrhythmia must carefully avoid systemic levels that could prompt coronary problems or other adverse side effects.
Accordingly, there is a need for a formulation that would locally and preferentially deliver anti-dysrhythmic treating agents to treat or prevent pelvic pain due to dysrhythmia, or to treat or improve infertility associated with dysrhythmia. The formulation should avoid blood levels of the treating agent high enough to cause detrimental side effects, while attaining sufficient local tissue levels of the treating agent to provide the desired therapeutic anti-dysrhythmic effect.